The 3 million Americans in U.S. nursing homes experience a staggering 2-3 million healthcare- associated infections each year. These infections result in over 150,000 readmissions and over 380,000 deaths annually. Nursing homes care for persons at high risk for infection due to the high prevalence of older age, wounds, medical devices, and comorbidities. Nursing homes also admit many residents that harbor multi- drug resistant organisms (MDROs), such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE), and emerging pan-resistant gram negative rods that cause serious and deadly disease. These pathogens carry associated risks for transmission among nursing home residents. Contact precautions and isolation, the mainstays of infection control in hospitals, do not provide a practical solution for nursing homes where socialization and a home-like environment are key components of recovery and quality of life. Decolonization strategies may provide a simple and low-cost solution to prevent infection and readmissions by reducing body surface bacteria that can cause infection. Our investigative team recently evaluated the effect of decolonization in a large pragmatic cluster- randomized clinical trial in hospital intensive care units and found that topical decolonization with antiseptc soap and nasal ointments reduced the burden of multi-drug resistant bacteria by over one-third and reduced bloodstream infections by nearly one-half. We will build on this experience to tailor a decolonization protocol to nursing home routines. We will test the hypothesis that decolonization might protect nursing home residents from infection and hospital readmission. We will also evaluate its potential benefit in decreasing the bioburden of multi-drug resistant organisms. The PROTECT Trial will rely upon a multi-disciplinary team of researchers with expertise in infectious diseases, infection prevention, geriatrics, nursing home care and administration, nursing education, and biostatistics to conduct a large cluster-randomized trial of decolonization in nursing homes that has the potential to decrease the substantial morbidity due to healthcare-associated infections in this vulnerable population.